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Pregnane X receptor knockout mice display aging-dependent wearing of articular cartilage.

Azuma K, Casey SC, Urano T, Horie-Inoue K, Ouchi Y, Blumberg B, Inoue S - PLoS ONE (2015)

Bottom Line: Here we report that systemic deletion of PXR results in aging-dependent wearing of articular cartilage of knee joints.Histomorphometrical analysis showed remarkable reduction of width and an enlarged gap between femoral and tibial articular cartilage in PXR knockout mice.We hypothesized that genes induced by SXR in chondrocytes have a protective effect on articular cartilage and identified Fam20a (family with sequence similarity 20a) as an SXR-dependent gene induced by the known SXR ligands, rifampicin and vitamin K2.

View Article: PubMed Central - PubMed

Affiliation: Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

ABSTRACT
Steroid and xenobiotic receptor (SXR) and its murine ortholog, pregnane X receptor (PXR), are nuclear receptors that are expressed at high levels in the liver and the intestine where they function as xenobiotic sensors that induce expression of genes involved in detoxification and drug excretion. Recent evidence showed that SXR and PXR are also expressed in bone tissue where they mediate bone metabolism. Here we report that systemic deletion of PXR results in aging-dependent wearing of articular cartilage of knee joints. Histomorphometrical analysis showed remarkable reduction of width and an enlarged gap between femoral and tibial articular cartilage in PXR knockout mice. We hypothesized that genes induced by SXR in chondrocytes have a protective effect on articular cartilage and identified Fam20a (family with sequence similarity 20a) as an SXR-dependent gene induced by the known SXR ligands, rifampicin and vitamin K2. Lastly, we demonstrated the biological significance of Fam20a expression in chondrocytes by evaluating osteoarthritis-related gene expression of primary articular chondrocytes. Consistent with epidemiological findings, our results indicate that SXR/PXR protects against aging-dependent wearing of articular cartilage and that ligands for SXR/PXR have potential role in preventing osteoarthritis caused by aging.

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Age-dependent wearing of articular cartilage of the knee joint.(A) Width of lateral articular cartilage of the tibia in 4-month-old wild type (WT; n = 8) and PXR knockout (KO; n = 8) mice, 8 month-old wild type (WT; n = 6) and PXR knockout (KO; n = 6) mice, and 13 month-old wild type (WT; n = 5) and PXR knockout (KO; n = 4) mice is shown. (B) Gap between femoral and tibial articular cartilage of 8-month-old wild-type (WT; n = 6) and PXR knockout (KO; n = 6) mice and 13 month-old wild-type (WT; n = 5) and PXR knockout (KO; n = 4) mice are shown. **P < 0.01.
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pone.0119177.g002: Age-dependent wearing of articular cartilage of the knee joint.(A) Width of lateral articular cartilage of the tibia in 4-month-old wild type (WT; n = 8) and PXR knockout (KO; n = 8) mice, 8 month-old wild type (WT; n = 6) and PXR knockout (KO; n = 6) mice, and 13 month-old wild type (WT; n = 5) and PXR knockout (KO; n = 4) mice is shown. (B) Gap between femoral and tibial articular cartilage of 8-month-old wild-type (WT; n = 6) and PXR knockout (KO; n = 6) mice and 13 month-old wild-type (WT; n = 5) and PXR knockout (KO; n = 4) mice are shown. **P < 0.01.

Mentions: To examine the effects of PXR on the articular cartilage, we utilized PXR knockout (PXRKO) mice. We evaluated the knee joints of relatively old 8-month-old and 13-month-old female PXRKO mice and female wild-type (WT) mice of the same age (Fig. 1). Histomorphometrical analysis of the lateral articular cartilage of the tibia revealed that the cartilage width of 8-month-old and 13-month-old PXRKO mice was significantly decreased compared with that of WT mice (Fig. 2A). The gap between the femoral and tibial lateral articular cartilage was significantly increased in 8-month-old and 13-month-old PXRKO mice relative to that of WT mice (Fig. 2B). These phenotypes are similar to those of osteoarthritis seen in elderly people. We then examined when this osteoarthritis-like phenotype develops in PXRKO mice. We evaluated the width of the lateral articular cartilage of the tibia in 4-month-old female PXRKO mice and WT mice. In contrast to aged mice, 4-month-old PXRKO mice displayed no significant differences in the width of the lateral articular cartilage compared with control mice (Fig. 2A). Compared with WT mice, the thickness of the articular cartilage of PXRKO mice did not increase between 4 months and 8 months, and it began to show wear between 8 months and 13 months. These results indicate that wearing of cartilage in PXRKO mice is an age-dependent pathological process similar to human osteoarthritis, although the damage in the surface of the cartilages was milder than expected considering their decreased width.


Pregnane X receptor knockout mice display aging-dependent wearing of articular cartilage.

Azuma K, Casey SC, Urano T, Horie-Inoue K, Ouchi Y, Blumberg B, Inoue S - PLoS ONE (2015)

Age-dependent wearing of articular cartilage of the knee joint.(A) Width of lateral articular cartilage of the tibia in 4-month-old wild type (WT; n = 8) and PXR knockout (KO; n = 8) mice, 8 month-old wild type (WT; n = 6) and PXR knockout (KO; n = 6) mice, and 13 month-old wild type (WT; n = 5) and PXR knockout (KO; n = 4) mice is shown. (B) Gap between femoral and tibial articular cartilage of 8-month-old wild-type (WT; n = 6) and PXR knockout (KO; n = 6) mice and 13 month-old wild-type (WT; n = 5) and PXR knockout (KO; n = 4) mice are shown. **P < 0.01.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4352085&req=5

pone.0119177.g002: Age-dependent wearing of articular cartilage of the knee joint.(A) Width of lateral articular cartilage of the tibia in 4-month-old wild type (WT; n = 8) and PXR knockout (KO; n = 8) mice, 8 month-old wild type (WT; n = 6) and PXR knockout (KO; n = 6) mice, and 13 month-old wild type (WT; n = 5) and PXR knockout (KO; n = 4) mice is shown. (B) Gap between femoral and tibial articular cartilage of 8-month-old wild-type (WT; n = 6) and PXR knockout (KO; n = 6) mice and 13 month-old wild-type (WT; n = 5) and PXR knockout (KO; n = 4) mice are shown. **P < 0.01.
Mentions: To examine the effects of PXR on the articular cartilage, we utilized PXR knockout (PXRKO) mice. We evaluated the knee joints of relatively old 8-month-old and 13-month-old female PXRKO mice and female wild-type (WT) mice of the same age (Fig. 1). Histomorphometrical analysis of the lateral articular cartilage of the tibia revealed that the cartilage width of 8-month-old and 13-month-old PXRKO mice was significantly decreased compared with that of WT mice (Fig. 2A). The gap between the femoral and tibial lateral articular cartilage was significantly increased in 8-month-old and 13-month-old PXRKO mice relative to that of WT mice (Fig. 2B). These phenotypes are similar to those of osteoarthritis seen in elderly people. We then examined when this osteoarthritis-like phenotype develops in PXRKO mice. We evaluated the width of the lateral articular cartilage of the tibia in 4-month-old female PXRKO mice and WT mice. In contrast to aged mice, 4-month-old PXRKO mice displayed no significant differences in the width of the lateral articular cartilage compared with control mice (Fig. 2A). Compared with WT mice, the thickness of the articular cartilage of PXRKO mice did not increase between 4 months and 8 months, and it began to show wear between 8 months and 13 months. These results indicate that wearing of cartilage in PXRKO mice is an age-dependent pathological process similar to human osteoarthritis, although the damage in the surface of the cartilages was milder than expected considering their decreased width.

Bottom Line: Here we report that systemic deletion of PXR results in aging-dependent wearing of articular cartilage of knee joints.Histomorphometrical analysis showed remarkable reduction of width and an enlarged gap between femoral and tibial articular cartilage in PXR knockout mice.We hypothesized that genes induced by SXR in chondrocytes have a protective effect on articular cartilage and identified Fam20a (family with sequence similarity 20a) as an SXR-dependent gene induced by the known SXR ligands, rifampicin and vitamin K2.

View Article: PubMed Central - PubMed

Affiliation: Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.

ABSTRACT
Steroid and xenobiotic receptor (SXR) and its murine ortholog, pregnane X receptor (PXR), are nuclear receptors that are expressed at high levels in the liver and the intestine where they function as xenobiotic sensors that induce expression of genes involved in detoxification and drug excretion. Recent evidence showed that SXR and PXR are also expressed in bone tissue where they mediate bone metabolism. Here we report that systemic deletion of PXR results in aging-dependent wearing of articular cartilage of knee joints. Histomorphometrical analysis showed remarkable reduction of width and an enlarged gap between femoral and tibial articular cartilage in PXR knockout mice. We hypothesized that genes induced by SXR in chondrocytes have a protective effect on articular cartilage and identified Fam20a (family with sequence similarity 20a) as an SXR-dependent gene induced by the known SXR ligands, rifampicin and vitamin K2. Lastly, we demonstrated the biological significance of Fam20a expression in chondrocytes by evaluating osteoarthritis-related gene expression of primary articular chondrocytes. Consistent with epidemiological findings, our results indicate that SXR/PXR protects against aging-dependent wearing of articular cartilage and that ligands for SXR/PXR have potential role in preventing osteoarthritis caused by aging.

Show MeSH
Related in: MedlinePlus